The present invention relates to improved medical procedures in which addition of a synthetic oxygen carrier in connection with autologous blood replacement (and, preferably, in connection with hemodilution) is used to reduce or eliminate the need for homologous blood.
More than 13 million units of blood are collected each year in the United States alone, and about 10 million of these units are transfused into 4 million recipients. Of the transfused units, about two-thirds are used during surgical procedures, and the remainder are used primarily for treating severe anemia or in emergency indications. Experience from clinical studies suggests that postoperative recovery can be shortened if hemoglobin concentrations are not allowed to fall to below 10 g/dL, the generally accepted indication for transfusion (Zauder, Anesth. Clin. North Amer 8:471-80 (1990)). This criterion, however, is currently being reevaluated due in part to a recent increase in awareness of the risks associated with homologous blood transfusion (NIH Consensus Conference JAMA 260:2700-2703 (1988)). This has also resulted in a renewed interest in the use of autologous blood transfusion techniques, in particular predonation and acute normovolemic hemodilution (ANH).
Although autologous blood transfusion (i.e., reinfusion of the patient's own blood) was first employed over 170 years ago, it was not until the early 1970s that its use became more widespread because of growing concerns about the transmission of hepatitis. More recently, interest in autologous transfusions on the part of both patients and physicians has been stimulated by the emergence of AIDS. Despite an increased awareness and acceptance of the benefits of autologous blood transfusion, recent studies have revealed the widespread underutilization of autologous predonation (which is estimated to represent only 2-5% of all units drawn nationwide).
The outcome of some surgical procedures may be improved by reducing blood viscosity prior to surgery. This can be accomplished with ANH at the start of an operation (Stehling et al. Transfusion 31:857 (1991)). ANH is a procedure whereby several units of blood are withdrawn from the patient at the beginning of surgery and simultaneously replaced with either a crystalloid or a colloid plasma volume expander. The basic mechanism that compensates for most of the decreased oxygen capacity of the diluted blood is the rise in cardiac output and increased organ blood flow, factors that result from the improved fluidity of blood (i.e., lower viscosity) at lower hematocrit levels (Messmer et al Eur. Surg. Res. 18:254-263 (1986)).
Predonation typically involves withdrawal of several units of a patient's blood during the six weeks prior to surgery. To avoid excessive anemia, the amount of blood that can be safely predonated in the weeks before surgery is limited, as is the amount of blood that can be removed during ANH.
One potential drawback of ANH and, to a lesser degree, predonation, is the loss of oxygen carrying capacity of the blood during surgery.
Quite apart from ANH and predonation, it has been suggested that red cell substitutes, or blood substitutes, could be used in place of homologous blood (i.e., blood from other humans) during surgery. Extensive research in the field of such blood substitutes over the past two decades has resulted in several candidate compositions. These include perfluorocarbon emulsions, such as Fluosol.TM. (Green Cross Corporation, Japan) and Oxygent.TM. (Alliance Pharmaceutical Corp., San Diego, USA), and hemoglobin compositions, such as those derived from human, animal, or recombinant sources. Traditional thinking has been that a red cell substitute would be given in volumes equal to the amount of whole blood that would be used for the same purpose.
Unfortunately, the use of such blood substitutes to replace blood used in transfusions has not been entirely satisfactory. Early studies using Fluosol, for example, as a blood substitute found that after blood loss, fluosal was "unnecessary in moderate anemia and ineffective in severe anemia." Gould, et al., New Engl. J. Med. 314:1653 (1986). In this study, the average increase in arterial oxygen content with the drug was only 0.7 ml/deciliter. Thus, it was believed that use of such fluorocarbon emulsions as blood substitutes would not provide a significant benefit in severely anemic patients. Indeed, although the U.S. Food & Drug Administration has now approved Fluosol for use as a perfusion agent during percutaneous transluminal coronary angioplasty (PTCA), it has to date refused to approve its use as a blood substitute for general use.
Another problem in using fluorocarbon emulsions and hemoglobin compositions as red cell substitutes or blood substitutes to compensate for blood loss from surgery, disease, or trauma is the relatively short half life of those materials in vivo. Healthy humans typically require about two weeks to manufacture new red cells and increase hematocrit to normal following blood loss. In contrast, the intravascular half life of fluorocarbon emulsions and hemoglobin substitutes in vivo, is typically less than 72 hours, often less than 24 hours. Thus, even if sufficient quantities of a red cell substitute are administered during and/or after surgery, for example, to provide adequate oxygen delivery, the oxygen carrying capacity will drop significantly long before the body can compensate by making new red cells.